Project Summary/Abstract Depression is a growing public health problem worldwide. The significance of the problem is compounded by the fact that up to 30% of patients do not adequately respond to currently available pharmacological treatment. As a result, electroconvulsive therapy (ECT), which is the most effective and has the most rapid onset of all FDA- approved therapies available for treatment-resistant depression, is widely used despite limitations, including requirement for repeated anesthesia and cognitive side effects. These drawbacks have stimulated interest in identifying the cellular and molecular mechanisms mediating its antidepressant action to guide development of improved circuit-based brain stimulation therapies for depression. Electroconvulsive seizures (ECS), an animal model of ECT, substantially increase expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, a region that has emerged as a critical locus for mediating the antidepressant effects of ECT. Multiple promoters govern Bdnf expression, yet ECS drives both acute and sustained BDNF production in hippocampus most potently from promoter I. These findings suggest that ECS-responsive, promoter I-expressing BDNF cells are critical components of hippocampal circuits that contribute to the antidepressant response. However, how ECS controls the function of these BDNF-expressing neurons, and how they mediate the antidepressant response is not known. We hypothesize that ECS triggers a cascade of epigenomic changes, which ultimately influence gene expression to control structure and function in neural circuits that facilitate ECT's robust antidepressant response. In this proposal we take a unique approach by using molecular-genetic strategies to selectively isolate BDNF-expressing neurons to profile the transcriptomic and epigenomic response to both acute and chronic ECS. Using these parallel sequencing techniques, this approach allows us to define a genome-wide epigenetic code of the antidepressant response specifically in a population of ECS responsive cells. Importantly, our analysis will assess differences across time to define acute versus chronic changes in gene expression that contribute to the antidepressant response, and will also evaluate changes between males and females, to evaluate how biological sex impacts these effects. This is significant because there have been noted influences of interactions between BDNF and biological sex on the susceptibility to and recovery from depression. In summary, our approach will define the transcriptional programs that are activated by ECS in a population of cells that are functionally linked to the antidepressant response, and are thus are expected to provide significant insight into the ECS-induced chromatin remodeling and gene regulation mechanisms that control behavior.